Development of a mouse model of brown fat dystrophia

棕色脂肪营养不良小鼠模型的建立

• 批准号: 10590670
• 负责人: Juan Sanchez-Gurmaches
• 金额: $ 19.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590670
• 关键词: AKT1 gene; AKT2 gene; Address; Adipocytes; Adult; Affect; Age; Bioenergetics; Biology; Biomedical Research; Brown Fat; Cells; Data; Development; Disease; Energy Metabolism; Energy consumption; FRAP1 gene; Fatty acid glycerol esters; Generations; Genomics; Goals; Growth; Growth Factor; Health; Homeostasis; Human; Knock-out; Laboratories; Lead; Medical center; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Mus; Obesity; Outcome; PIK3CG gene; Pathologic; Pediatric Hospitals; Phosphotransferases; Physiological; Physiology; Positioning Attribute; Potential Energy; Pre-Clinical Model; Production; Regulation; Reporter; Research; Resolution; Resources; Role; Scientist; Signal Transduction; Signaling Molecule; System; Techniques; Testing; Thermogenesis; Tissues; United States National Institutes of Health; adipocyte differentiation; animal model development; body system; human model; humanized mouse; in vivo Model; interdisciplinary approach; interest; metabolic phenotype; mouse model; novel therapeutic intervention; obesogenic; pre-clinical research; reproductive; response; virtual

Abstract/Project Summary Mice physiology is deeply affected by brown fat through its control of metabolic homeostasis and production of signaling molecules. However, the vast majority of humans do not have brown fat. This deeply bias the use of mice as a model of human physiology. A mouse model without BAT would allow us to undoubtably determine the putative roles of brown fat in metabolism, in other organ systems and to have a better, humanized, model for preclinical research. Following our mechanistic exploration of the role of growth factors/PI3K/mTOR signaling to understand brown fat formation and metabolism, we unexpectedly generated a mouse model with no discernable classic brown fat, which we call BAT-less mice. The BAT-less mice are born at normal mendelian ratios, fully viable, with normal reproductive capacity and the effects are 100% penetrant. Based on our exciting preliminary data, the central hypothesis for this application is that the complete lack of UCP1 expressing cells in BAT-less mice lead to distinct obesogenic effects compared to UCP1 knockouts. To test this hypothesis, we have developed a toolkit of unique in vivo models including new reporter mouse models and a multidisciplinary approach using whole mouse and tissue-clearing lineage tracing techniques, genomics and state of the art metabolic phenotyping techniques. In Aim 1, we will critically and unequivocally determine if all brown fat depots are lost in BAT-less at all developmental stages using a multi-reporter system tracking UCP1 expressing cells. In Aim 2, we will employ the BAT-less mice to test the contribution of BAT energy consumption to whole body metabolism and obesity propensity independently of UCP1. The BAT-less mice are anticipated to be useful to scientists in an array of fields with implications in multiple NIH institutes. Additionally, the BAT-less mice will be a step forward towards a more humanized, broadly useful, mouse model.

摘要/项目摘要 小鼠生理学通过控制代谢稳态和产生的棕色脂肪深处受到棕色脂肪的影响 信号分子。但是，绝大多数人没有棕色脂肪。这深深地偏见 小鼠作为人类生理的模型。没有蝙蝠的鼠标模型将使我们无疑确定 棕色脂肪在代谢，其他器官系统中的推定作用，并具有更好，人性化的模型 用于临床前研究。遵循我们对生长因子/pi3k/mtor的作用的机械探索 信号传导以了解棕色脂肪形成和代谢，我们意外地生成了一个用 没有可分辨的经典棕色脂肪，我们称之为无蝙蝠的老鼠。无蝙蝠的老鼠正常出生 Mendelian比率完全可行，具有正常的生殖能力，其影响为100％渗透剂。基于 我们令人兴奋的初步数据，该应用程序的中心假设是完全缺乏UCP1 与UCP1敲除相比，在无蝙蝠小鼠中表达细胞会导致明显的肥胖作用。测试 这个假设，我们开发了一个独特的体内模型工具包，包括新的记者鼠标模型 以及使用整个小鼠和组织清除谱系追踪技术，基因组学的多学科方法 和最先进的代谢表型技术。在AIM 1中，我们将批判性和明确地确定是否是否 所有棕色的脂肪库都使用多重腐蚀剂系统跟踪在所有发育阶段都在所有发育阶段丢失 UCP1表达细胞。在AIM 2中，我们将使用无蝙蝠的小鼠来测试蝙蝠能量的贡献 对全身代谢和肥胖倾向的消费独立于UCP1。无蝙蝠的老鼠是 预计对多个NIH研究所的一系列领域中的科学家有用。此外， 无蝙蝠的小鼠将是向更具人性化，有用的鼠标模型向前迈出的一步。